This invention is directed to the tetradecapeptides ##STR2## in which Y is Gly or D-Ala as well as to their pharmaceutically acceptable acid addition salts and to intermediates produced during the synthesis of the tetradecapeptides.
Somatostatin (also known as somatotropin release inhibiting factor) is a tetradecapeptide of the formula ##STR3## This tetradecapeptide was isolated from ovine hypothalamic extracts and was found to be active in inhibiting the secretion of growth hormone (GH), also known as somatotropin. In this regard, see P. Brazeau, W. Vale, R. Burgus, N. Ling, M. Butcher, J. Rivier, and R. Guillemin, Science, 179, 77 (1973).
D-Ala.sup.2 -somatostatin is the subject of co-pending U. S. application Ser. No. 628,180 filed Nov. 3, 1975.
D-Lys.sup.4 -somatostatin is disclosed in L. Farland et al., Molecular and Cellular Endocrinology, 4, 79-86 (1976).
The tetradecapeptides of this invention have the formula defined above and include the non-toxic acid addition salts thereof. Their structures differ from that of somatostatin by the presence of a D-lysine residue in position 4 in place of an L-lysine residue, and, insofar as one of the tetradecapeptides is concerned, by the presence of a D-alanine residue in position 2 in place of a glycine residue. For convenience sake, the tetradecapeptides of this invention can be referred to as D-Lys.sup.4 -somatostatin and as D-Ala.sup.2, D-Lys.sup.4 -somatostatin.
Thus, this invention is directed to a compound selected from those of the formula ##STR4## and pharmaceutically acceptable non-toxic acid addition salts, and R-L-Ala-Y-L-Cys(R.sub.1)-D-Lys(R.sub.2)-L-Asn-L-Phe-L-Phe-L-Trp(R.sub.5)-L -Lys(R.sub.2)-L-Thr(R.sub.3)-L-Phe-L-Thr(R.sub.3)-L-Ser(R.sub.4)-L-Cys(R.su b.1)-X; in which
Y is Gly or D-Ala; PA1 R is hydrogen or an .alpha.-amino protecting group; PA1 R.sub.1 is hydrogen or a thio protecting group; PA1 R.sub.2 is hydrogen or an .epsilon.-amino protecting group; PA1 R.sub.3 and R.sub.4 each are hydrogen or a hydroxy protecting group; PA1 R.sub.5 is hydrogen or formyl; and PA1 X is hydroxy or ##STR5## in which the resin is polystyrene; with the proviso that, when X is hydroxy, each of R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 is hydrogen, and, when X is ##STR6## each of R, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 is other then hydrogen. PA1 H-l-ala-Gly-L-Cys-D-Lys-L-Asn-L-Phe- PA1 L-phe-L-Trp-L-Lys-L-Thr-L-Phe-L-Thr- PA1 L-ser-L-Cys-OH; PA1 H-l-ala-D-Ala-L-Cys-D-Lys-L-Asn-L- PA1 Phe-L-Phe-L-Trp-L-Lys-L-Thr-L-Phe- PA1 L-thr-L-Ser-L-Cys-OH; PA1 N-(boc)-l-ala-Gly-L-(PMB)Cys-D-(CPOC)- PA1 Lys-L-Asn-L-Phe-L-Phe-L-Trp-L-(CPOC)- PA1 Lys-L-(Bzl)Thr-L-Phe-L-(Bzl)Thr-L- ##STR7## and N-(BOC)-L-Ala-D-Ala-L-(PMB)Cys-D- PA1 (cpoc)lys-L-Asn-L-Phe-L-Phe-L-Trp-L- ##STR8##